Crizotinib enhances anti-CD30-LDM induced antitumor efficacy in NPM-ALK positive anaplastic large cell lymphoma

Crizotinib enhances anti-CD30-LDM induced antitumor efficacy in NPM-ALK positive anaplastic large cell lymphoma

April 28, 2019

Abstract

Combining antibody-drug conjugates (ADCs) with targeted small-moleculeinhibitors can enhance antitumor effects beyond those attainable with monotherapy. In this study, we investigated the therapeutic combination of a CD30-targeting ADC (anti-CD30-lidamycin [LDM]) with a small-molecule inhibitor (crizotinib) of nucleophosmin-anaplastic lymphoma kinase NPM-ALK in CD30+/ALK+ anaplastic large cell lymphoma (ALCL). In vitro, anti-CD30-LDM showed strong synergistic antiproliferative activity when combined with crizotinib. Furthermore, treatment with anti-CD30-LDM plus crizotinib resulted in a stronger induction of cell apoptosis than monotherapy with either treatment. Western blot analysis revealed that ERK1/2 phosphorylation was increased in response to anti-CD30-LDM-induced DNA damage. Interestingly, the addition of crizotinib inhibited the expression of phosphorylated ERK1/2 and further augmented anti-CD30-LDM-mediated apoptosis, providing a potential synergistic mechanism for DNA-damaging agents combined with NPM-ALK inhibitors. In Karpas299 and SU-DHL-1 xenograft models, anti-CD30-LDM plus crizotinib was more effective in inhibiting tumor growth than either treatment alone. This research demonstrated for the first time that the combination of anti-CD30-LDM and crizotinib exhibits a synergistic inhibitory effect in tumor cells. These results provide scientific support for future clinical evaluations of anti-CD30-LDM, or other DNA-damaging agents, combined with NPM-ALK inhibitors.

Authors: Rong Wangab1 Liang Lia1 Aijun Duana Yi Lia Xiujun Liua Qingfang Miaoa Jianhua Gonga Yongsu Zhena

Influence Factor: 6.491

Citation: Cancer Lett 448, 84-93 (2019)

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